tetano
Editor, Senior Moderator
Hum Genet
. 2021 Jun 21.
doi: 10.1007/s00439-021-02305-z. Online ahead of print.
Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation
Yulin Dai[SUP] #[/SUP][SUP] 1 [/SUP], Junke Wang[SUP] #[/SUP][SUP] 2 [/SUP], Hyun-Hwan Jeong[SUP] 1 [/SUP], Wenhao Chen[SUP] 3 4 [/SUP], Peilin Jia[SUP] 1 [/SUP], Zhongming Zhao[SUP] 5 6 7 [/SUP]
Affiliations
Abstract
The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~ 80% asymptomatic or mild cases and ~ 5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis, and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single-cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on lung, and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung-resident memory CD8[SUP]+[/SUP] T (T[SUB]RM[/SUB]) cells, we found a 2.24-fold decrease of cell proportion among CD8[SUP]+[/SUP] T cells and lower expression of CXCR6 in the severe patients than moderate patients. Pro-inflammatory transcriptional programs were highlighted in the T[SUB]RM[/SUB] cellular trajectory from moderate to severe patients. CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung T[SUB]RM[/SUB] cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis.
. 2021 Jun 21.
doi: 10.1007/s00439-021-02305-z. Online ahead of print.
Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation
Yulin Dai[SUP] #[/SUP][SUP] 1 [/SUP], Junke Wang[SUP] #[/SUP][SUP] 2 [/SUP], Hyun-Hwan Jeong[SUP] 1 [/SUP], Wenhao Chen[SUP] 3 4 [/SUP], Peilin Jia[SUP] 1 [/SUP], Zhongming Zhao[SUP] 5 6 7 [/SUP]
Affiliations
- PMID: 34155559
- DOI: 10.1007/s00439-021-02305-z
Abstract
The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~ 80% asymptomatic or mild cases and ~ 5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis, and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single-cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on lung, and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung-resident memory CD8[SUP]+[/SUP] T (T[SUB]RM[/SUB]) cells, we found a 2.24-fold decrease of cell proportion among CD8[SUP]+[/SUP] T cells and lower expression of CXCR6 in the severe patients than moderate patients. Pro-inflammatory transcriptional programs were highlighted in the T[SUB]RM[/SUB] cellular trajectory from moderate to severe patients. CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung T[SUB]RM[/SUB] cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis.